Sepsis results in the concurrent activation of inflammatory and procoagulant pathways. Bacterial products and
proinflammatory cytokines trigger the coagulation system primarily via induction of tissue factor. During sepsis, activation
of coagulation is accompanied by impaired function of major anticoagulant mechanisms, including antithrombin, the
protein C system and fibrinolysis. Protease activated receptors (PARs) form the molecular connection between coagulation
and inflammation, and especially PAR1 seems to play an eminent role in sepsis pathogenesis. Activated protein C
(APC) can cleave PAR1 when associated with either the endothelial protein C receptor (EPCR) or CD11b/CD18, resulting
in broad cytoprotective effects mediated by sphingosine 1 phosphate (S1P) receptor 1 (S1P1). In contrast, activation of
PAR1 by high dose thrombin results in barrier disruptive effects in endothelial cells via an S1P3 dependent mechanism.
Recombinant APC protects against mortality in experimental endotoxemia and sepsis by effects that can be mediated by
either EPCR - PAR1 dependent (endothelial cells, dendritic cells) or CD11b/CD18 – PAR1 dependent (macrophages)
mechanisms. These protective APC effects do not rely on the anticoagulant properties of this protein. APC mutants that
lack anticoagulant properties but retain the capacity to activate PAR1 are promising new drugs for sepsis treatment.
Keywords: Activated protein C, coagulation, inflammation, protease activated receptors, sepsis, TF, endothelial cells, dendritic cells, Toll-like receptors, endotoxemia
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